Abbas orabi.translating evidence

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  • 1. Translating evidence into patients benefits By: Abbas Oraby
  • 2. Drugs in this classSulfonylureas were the first widely used oral anti-hyperglycaemicmedications. Many types of these pills have been marketed but not allremain available. Acetohexamide Glipizide Chlorpropamide Gliclazide Glibenclamide (glyburide) Tolbutamide Gliquidone Tolazamide Glyclopyramide
  • 3. MECHANISMS OF ACTION OF SUs
  • 4. Insulin release It involves 3 main steps : 1. Translocation of insulin granules. 2. Docking of insulin granules. 3. Fusion of insulin granules. 8
  • 5. Microtubules form a network radiating from theperinuclear region outwords . The framework provides the mechanical pathway along which secretory granules move toward the exocytic sites close to the plasma membrane. It gives the way but not the force 10
  • 6. Ca+ is essential for almost all stepsinvolved in insulin release, thus factorsincreasing intracellular Ca+ will augmentinsulin release.Mechanisms involved inincreasing intra-cytoplasmic Ca+ : Ca-influx from outside. Inhibition of Ca-reuptake by Ca++ Store intracellulas stores. x Increased Ca-sensitivity. 12
  • 7. Increased intracellular Ca+ is essential for granules translocation and fusion hence release of insulin. ATP-sensitive Voltage-gate Ca Glucose K+ channel channel 6 GLUT2 X Fusion K retention 4 Glucose 3 Depolarization Ca+ 2Glucokinase 1 5 G-6-P ATP Translocation Each B-cell contains up to 500 Ca channels 13
  • 8. Mechanisms of action cont. The rise in intracellular calcium leads to increased fusion of insulin granules with the cell membrane, and therefore increased secretion of (pro)insulin. There is some evidence that sulfonylureas also sensitize -cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis and decrease clearance of insulin by the liver.
  • 9. Insulin Secretion (Glimepiride)Glimepiride binds to the 65 kDa subunit of the sulfonylureareceptor; glibenclamide binds to the 140 kDa subunit
  • 10. Therapeutic actions Pancreas Sulfonylurea + Impaired glimepiride Insulin secretion Insulin resistance Increased Decreased glucose glucose production Hyperglycaemia uptakeLiver Muscle Metformin 16
  • 11. Attributes of sulfonylureas How they work Enhance insulin secretion Expected HbA1c 1 to 2% reduction Adverse events Hypoglycemia* (but severe episodes are infrequent) Weight effects ~ 2 kg weight gain common when therapy initiated CV effects None substantiated by UKPDS or ADVANCE study* Substantially greater risk of hypoglycemia with chlorpropamide and glibenclamide (glyburide) than other second- generation sulfonylureas (gliclazide, glimepiride, glipizide) 17Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
  • 12. IDF Global Guideline for Type 2 Diabetes Diagnosis Lifestyle intervention then metformin HbA1c 6.5 % Add sulfonylurea HbA1c 6.5 % HbA1c 6.5 %*Alternatively, start Add thiazolidinedione* Add insulinthiazolidinedione beforesulfonylurea,and sulfonylurea later. HbA1c 7.5 % HbA1c 7.0 % Start insulin intensify insulin Meal-time + basal insulin + metformin thiazolidinedione IDF. Global Guideline for Type 2 Diabetes. 2005
  • 13. ADA and EASD algorithm for the management of type 2 diabetes Tier 1: Well validated therapies Lifestyle and At Lifestyle and met + intensive diagnosis: met + basal insulin Lifestyle insulin + metformin Lifestyle and met + SUa Step 1 Step 2 Step 3 Tier 2: Less well validated therapies Lifestyle and met + pio Lifestyle and met No hypoglycaemia Oedema/CHF + pio + SUa Bone loss Lifestyle and met + GLP-1 agonistb Lifestyle and No hypoglycaemia Weight loss met + basal insulin Nausea/vomiting Reinforce lifestyle interventions every visit and check HbA1C every 3 months until HbA1C is